These studies are designed to provide preclinical information for the development of medications to be used in the treatment of drug abuse and drug abuse-related toxicities. The primary focus of this work is to determine pharmacological means for modulating behavioral and toxic actions of abused compounds, and to evaluate new chemical entities (synthesized in house and from outside sources) for safety and efficacy in the design of potential rational treatment strategies. Work in this area is also expected to provide increased understanding of the mechanisms of action of drugs of abuse. The primary findings and implications for the current year are: (1) We have extended initial observations that certain sigma-receptor ligands can antagonize some of the acute behavioral effects of cocaine by demonstrating this effect with a highly selective sigma ligand and by showing that this compound can also attenuate the behavioral effects of repeated cocaine exposure (sensitization) and cocaine-induced convulsions. We have also found that certain sigma ligands bind to the dopamine transporter. Ongoing studies are focusing on identifying significant features of sigma ligands that imbue them with the ability to block effects of cocaine and defining a mechanism for the cocaine blockade. A host of sigma ligands, some with excellent affinity and selectivity have been synthesized to aid in this effort. (2) A variety of compounds proposed by NIDA as potential treatments for cocaine abuse are being examined in preclinical screens for safety and efficacy as potential treatments for cocaine abuse. (3) Psychomotor stimulant effects of abused drugs like cocaine may be amenable to pharmacological antagonism through glutamate receptors. We have discovered some such compounds with efficacy as antagonists of the stimulant effects of cocaine and of methamphetamine and have uncovered differences among these compounds which should help shed light on the interactions between dopaminergic and excitatory amino acid pathways. (4) In accord with clinical experience, we have used a model developed in our lab of cocaine-induced convulsions that are relatively insensitive to standard anticonvulsants to discover novel and efficacious treatments for drug-resistant cocaine toxicities. Thus far, a host of glutamate antagonists have been shown to be effective and some appear to have a reasonable margin of safety for this therapeutic endpoint. Two classes of compounds have been identified for further drug development, low affinity NMDA antagonists and functional antagonists of the glycine-linked site of the NMDA receptor. (5) Pharmacological studies have tentatively identified a population of dopamine D1 receptors in the periphery that may be linked to the acute lethal effects of cocaine. Compounds necessary for further investigations in this area have been synthesized and structure-activity relationships, and in vitro and in vivo pharmacological characterization of these compounds is underway.